Substituted oximes and hydrazones as neurokinin antagonists

ABSTRACT

Compound represented by the structural formula  
                 
 
     or a pharmaceutically acceptable salt thereof, wherein:  
     a is 0-3;  
     b, d and e are 0-2;  
     R is H, alkyl, F or —OR 6 ;  
     A is an optionally substituted oxime or hydrazone;  
     d is not 0 and X is a bond, —C(O)—, —O—, —NR 9 —, —S(O) e —, —N(R 6 )C(O)—, —C(O)N(R 6 )—, —OC(O)NR 6 —, —OC(═S)NR 6 —, —N(R 6 )C(═S)O—, —S(O) 2 N(R 6 )—, —N(R 6 )S(0) 2 —, —N(R 6 )C(O)O—, —OC(O)— or —N(R 6 )C(O)NR 7 —; or d is 0 and X is a bond or —NR 6 —;  
     T is H, aryl, heterocycloalkyl or heteroaryl;  
     Q is phenyl, naphthyl or heteroaryl;  
     R 6  is H, alkyl, hydroxyalkyl, alkoxyalkyl, phenyl, and benzyl;  
     R 9  is R 6  or —OR 6    
     R 6a , R 7a , R 8a  and R 9a  are H or alkyl;  
     Z is a nitrogen-containing heterocyclo group, e.g., piperidinyl, substituted by a heterocyclo- or heterocycloalkyl group;  
     wherein phenyl, benzyl, aryl, heterocycloalkyl, heteroaryl and cycloalkyl groups are optionally substituted; methods of treating diseases such as asthma, cough, bronchospasm, depression, emesis, imflammatory diseases, and gastrointestinal disorders with said compounds, and pharmaceutical compositions comprising said compounds are disclosed.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a genus of substituted oximesand hydrazones useful as antagonists of tachykinin receptors, inparticular as antagonists of the neuropeptides neurokinin-1 receptor(NK₁) and/or neurokinin-2 receptor (NK₂) and/or neurokinin-3 receptor(NK₃).

[0002] Neurokinin receptors are found in the nervous system and thecirculatory system and peripheral tissues of mammals, and therefore areinvolved in a variety of biological processes. Neurokinin receptorantagonists are consequently expected to be useful in the treatment orprevention of various mammalian disease states, for example asthma,cough, bronchospasm, inflammatory diseases such as arthritis, centralnervous system conditions such as migraine and epilepsy, nociception,depression, and various gastrointestinal disorders such as Crohn'sdisease.

[0003] In particular, NK₁ receptors have been reported to be involved inmicrovascular leakage and mucus secretion, and NK₂ receptors have beenassociated with smooth muscle contraction, making NK₁ and NK₂ receptorantagonists especially useful in the treatment and prevention of asthma.

[0004] Substituted oxime and hydrazone NK₁ and NK₂ receptor antagonistshave previously been disclosed in U.S. Pat. No. 5,696,267, U.S. Pat. No.5,688,960, and U.S. Pat. No. 5,789,422.

SUMMARY OF THE INVENTION

[0005] Compounds of the present invention are represented by the formulaI

[0006] or a pharmaceutically acceptable salt thereof, wherein:

[0007] a is 0, 1, 2 or 3;

[0008] b and d are independently 0, 1 or 2;

[0009] R is H, C₁₋₆ alkyl, —OR⁶ or —F;

[0010] A is ═N—OR¹ or ═N—N(R²)(R³);

[0011] when d is not 0, X is a bond, —C(O)—, —O—, —NR⁹—, —S(O)_(e)—,—N(R⁶)C(O)—, —C(O)N(R⁶)—, —OC(O)NR⁶—, —OC(═S)NR⁶—, —N(R⁶)C(═S)O—,—S(O)₂N(R⁶)—, —N(R⁶)S(O)₂—, —N(R⁶)C(O)O—, —OC(O)— or —N(R⁶)C(O)NR⁷; and

[0012] when d is 0, X is a bond or —NR⁶—;

[0013] T is H, R⁴-aryl, R⁴-heterocycloalkyl or R⁴-heteroaryl;

[0014] Q is R⁵-phenyl, R⁵-naphthyl or R⁵-heteroaryl;

[0015] R¹ is H, C₁₋₆ alkyl, —(C(R⁶)(R⁷))_(n)—G, —G²,—(C(R⁶)(R⁷))_(p)—M—(C(R¹³)(R¹⁴))_(n)—G or—(C(R⁶)(R⁷))_(p)—M—(R⁴—heteroaryl);

[0016] R² and R³ are independently selected from the group consisting ofH, C₁₋₆ alkyl, —(C(R⁶)(R⁷))_(n)—G, —G² and —S(O)_(e)R¹³; or R² and R³,together with the nitrogen to which they are attached, form a ring of 5to 6 members, wherein 0, 1 or 2 ring members are selected from the groupconsisting of —O—, —S— and —N(R¹⁹)—;

[0017] R⁴ and R⁵ are independently 1-3 substituents independentlyselected from the group consisting of H, halogeno, —OR⁶, —OC(O)R⁶,—OC(O)N(R⁶)(R⁷), —N(R⁶)(R⁷), C₁₋₆ alkyl, —CF₃, —C₂F₅, —COR⁶, —CO₂R⁶,—CON(R⁶)(R⁷), —S(O)_(e)R¹³, —CN, —OCF₃, —OCHF₂, —NR⁶CO₂R¹⁶, —NR⁶COR⁷,—NR⁸CON(R⁶)(R⁷), NO₂, —N(R⁶)S(O)₂R¹³ or —S(O)₂N(R⁶)(R⁷); or adjacent R⁴substituents or adjacent R⁵ substituents can form a —O—CH₂—O— group;

[0018] R⁶, R⁷, R⁸, R¹³ and R¹⁴ are independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₂-C₆ hydroxyalkyl, C₁-C₆ alkoxy-C₁-C₆alkyl, R¹⁵-phenyl, and R¹⁵-benzyl;

[0019] R⁹ is independently selected from the group consisting of R⁶ and—OR⁶;

[0020] or R⁶ and R⁷, or R⁷ and R⁹, together with the nitrogen to whichthey are attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ringmembers are selected from the group consisting of —O—, —S— and —N(R¹⁹)—;

[0021] R^(6a), R^(7a), R^(8a), R^(9a), R¹⁰ and R^(10a) are independentlyselected from the group consisting of H and C¹⁻⁶ alkyl;

[0022] R¹⁵ is 1 to 3 substituents independently selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio,halogeno, —CF₃, —C₂F₅, —COR¹⁰, —CO₂R¹⁰, —C(O)N(R¹⁰)₂, —S(O)_(e)R^(10a),—CN, —N(R¹⁰)COR¹⁰, —N(R¹⁰)CON(R¹⁰)₂ and —NO_(2;)

[0023] R¹⁶ is C₁₋₆ alkyl, R¹⁵-phenyl or R¹⁵-benzyl;

[0024] R¹⁹ is H, C₁-C₆ alkyl, —C(O)N(R¹⁰)₂ or —CO₂R¹⁰;

[0025] n and p are independently 1-6;

[0026] G is selected from the group consisting of H, R⁴-aryl,R⁴-hetero-cycloalkyl, R⁴-heteroaryl, R⁴-cycloalkyl, —CH₂F, —CHF₂, —CF₃,—OR⁶, —N(R⁶)(R⁷), —COR⁶ —CO₂R⁶, —CON(R⁷)(R⁹), —S(O)_(e)R¹³, —NR⁶CO₂R¹⁶,—NR⁶COR⁷, —NR⁸CON(R⁶)(R⁷), —N(R⁶)S(O)₂R¹³, —N(R⁶)S(O)₂N(R³³)(R³⁴),—S(O)₂N(R⁶)(R⁷), —OC(O)R⁶, —OC(O)N(R⁶)(R⁷), —C(═NOR⁸)N(R⁶)(R⁷),—C(═NR²⁵)N(R⁶)(R⁷), —N(R⁸)C(═NR²⁵)N(R⁶)(R⁷), —CN, —C(O)N(R⁶)OR⁷, and—C(O)N(R⁹)-(R⁴-heteroaryl), provided that when n is 1, G is not —OH or—N(R⁶)(R⁷);

[0027] M is selected from the group consisting of a double bond, —O—,—N(R⁶)—, —C(O)—, —C(R⁶)(OR⁷)—, —C(R⁸)(N(R⁶)(R⁷))—, —C(═NOR⁶)N(R⁷)—,—C(N(R⁶)(R⁷))═NO—, —C(═NR²⁵)N(R⁶)—, —C(O)N(R⁹)—, —N(R⁹)C(O)—,—C(═S)N(R⁹)—, —N(R⁹)C(═S)—and —N(R⁶)C(O)N(R⁷)—, provided that when n is1, G is not OH or —NH(R⁶); and when p is 2-6, M can also be—N(R⁶)C(═NR²⁵)N(R⁷)— or —OC(O)N(R⁶)—;

[0028] G² is R⁴-aryl, R⁴-heterocycloalkyl, R⁴-heteroaryl, R⁴-cycloalkyl,—COR⁶, —CO₂R¹⁶, —S(O)₂N(R⁶)(R⁷) or —CON(R⁶)(R⁷);

[0029] e is 0, 1 or 2, provided that when e is 1 or 2, R¹³ and R^(10a)are not H;

[0030] R²⁵ is H, C₁-C₆ alkyl, —CN, R¹⁵-phenyl or R¹⁵-benzyl;

[0031] g, h and j are independently 0-2;

[0032] k is1-4;

[0033] X¹ is —O—, —S—or —NR⁹—;

[0034] J is ═O, ═S, ═NR⁹, ═NCN or ═NOR¹;

[0035] J¹ and J² are independently selected from the group consisting oftwo hydrogen atoms, ═O, ═S, ═NR⁹ and ═NOR¹;

[0036] R²⁶, R²⁷ and R²⁹ are independently selected from the groupconsisting of H, C₁₋₆ alkyl, —(C(R⁶)(R⁷))_(n)—G, —G², —^(C(O)—(C(R)⁸)(R⁹))^(n)—G and —S(O)_(e)R¹³⁻;

[0037] R²⁸ is H, —(C(R⁶)(R⁷))_(t)—G or —CON(R⁶)(R⁷);

[0038] t is 0, 1, 2 or 3, provided that when j is 0, t is 1, 2 or 3;

[0039] R³⁰ is 1-3 substituents independently selected from the groupconsisting of H, halogeno, —OR⁶, —OC(O)R⁶, —OC(O)N(R⁶)(R⁷), —(R⁶)(R⁷),C₁₋₆ alkyl, —CF₃, —C₂F₅, —COR⁶, —CO₂R₆, —CON(R⁶)(R⁷), —S(O)_(e)R¹³, —CN,—OCF₃, —NR⁶CO₂R¹⁶, —NR⁶COR⁷, —NR⁸CON(R⁶)(R⁷), NO₂, —N(R⁶)S(O)₂R¹³ or—S(O)₂N(R⁶)(R⁷); or adjacent R³⁰ substituents can form a —O—CH₂—O—group;

[0040] R³¹ is independently selected from the group consisting of H andC₁-C₆ alkyl;

[0041] R³² is independently selected from the group consisting of H, —OHand C₁-C₆ alkoxy; and

[0042] R³³ and R³⁴ are independently selected from the group consistingof H, C₁-C₆ alkyl, R¹⁵-phenyl and R¹⁵-benzyl.

[0043] Preferred are compounds of formula I wherein X is —O—, —C(O)—, abond, —NR⁶—, —S(O)_(e)—, —N(R⁶)C(O)—, —OC(O)NR⁶ or —C(═NOR¹)—. Morepreferred are compounds of formula I wherein X is —O—, —NR⁶—,—N(R⁶)C(O)— or —C(O)NR⁶. Additional preferred definitions are: b is 1 or2 when X is —O— or —N(R⁶)—; b is 0 when X is —N(R⁶)C(O)—; and d is 1 or2. T is preferably R⁴-aryl, with R⁴-phenyl being more preferred. Alsopreferred are compounds wherein R^(6a), R^(7a), R^(8a) and R^(9a) areindependently hydrogen, hydroxyalkyl or alkoxyalkyl, with hydrogen beingmore preferred. Especially preferred are compounds wherein R^(8a) andR^(9a) are each hydrogen, d and b are each 1, X is —O—, —NR⁶—,—N(R⁶)C(O)— or —OC(O)NR⁶, T is R⁴-aryl and R⁴ is two substituentsselected from C₁-C₆ alkyl, halogeno, —CF₃ and C₁-C₆ alkoxy.

[0044] Also preferred are compounds of formula I wherein R is hydrogen.Q is preferably R⁵-phenyl; an especially preferred definition for Q isR⁵-phenyl, wherein R⁵ is two halogeno substituents.

[0045] Preferred are compounds of formula I wherein A is ═N—R¹. R¹ ispreferably H, alkyl, —(CH₂)_(n)—G, —(CH₂)_(p)—M—(CH₂)_(n)—G or—C(O)N(R⁶)(R⁷), wherein M is —O— or —C(O)N(R⁹)—and G is —CO₂R⁶, —OR⁶,—C(O)N(R⁷)(R⁹), —C(═NOR⁸)N(R⁶)(R⁷), —C(O)N(R⁹)(R⁴-heteroaryl) orR⁴-heteroaryl. When A is ═N—N(R²)(R³), R² and R³ are independentlypreferably H, C₁-C₆ alkyl, —(C(R⁶)(R⁷))_(n)—G or G².

[0046] Preferred definitions of Z are

[0047] Variables g and h are preferably each 1; J is preferably ═O; j ispreferably 0; k is preferably 1 or 2; and R²⁸ is preferably H.

[0048] A more preferred defintion of Z is

[0049] wherein k is preferably 1 or 2.

[0050] This invention also relates to the use of a compound of formula Iin the treatment of for example respiratory diseases such as chroniclung disease, bronchitis, pneumonia, asthma, allergy, cough,bronchospasm; inflammatory diseases such as arthritis and psoriasis;skin disorders such as atopic dermatitis and contact dermatitis;ophthamalogical disorders such as retinitis, ocular hypertension andcataracts; addictions such as alcohol dependence and stress relateddisorders; central nervous system conditions such as anxiety, migraine,epilepsy, nociception, emesis, depression, psychosis, schizophrenia,Alzheimer's disease, AIDs related dementia and Towne's disease;gastrointestinal disorders such as Crohn's disease and colitis; bladderdisorders; atherosclerosis; fibrosing disorders; and obesity.

[0051] In another aspect, the invention relates to a pharmaceuticalcomposition comprising a compound of formula I in a pharmaceuticallyacceptable carrier. The invention also relates to the use of saidpharmaceutical composition in the treatment of the mammalian diseasestates listed above.

DETAILED DESCRIPTION

[0052] As used herein, the term “alkyl” means straight or branched alkylchains. “Lower alkyl” refers to alkyl chains of 1-6 carbon atoms and,similarly, lower alkoxy refers to alkoxy chains of 1-6 carbon atoms.

[0053] “Cycloalkyl” means cyclic alkyl groups having 3 to 6 carbonatoms.

[0054] “Aryl” means phenyl, naphthyl, indenyl, tetrahydronaphthyl,indanyl, anthracenyl or fluorenyl.

[0055] “Halogeno” refers to fluoro, chloro, bromo or iodo atoms.

[0056] “Heterocycloalkyl” refers to 4- to 6-membered saturated ringscomprising 1 to 3 heteroatoms independently selected from the groupconsisting of —O—, —S— and —N(R¹⁹)—, with the remaining ring membersbeing carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.R⁴-heterocycloalkyl refers to such groups wherein substitutable ringcarbon atoms have an R⁴ substituent.

[0057] “Heteroaryl” refers to 5- to 10-membered single or benzofusedaromatic rings comprising 1 to 4 heteroatoms independently selected fromthe group consisting of —O—, —S— and —N═, provided that the rings do notinclude adjacent oxygen and/or sulfur atoms. Examples of single-ringheteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl,pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl,thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl.Examples of benzofused heteroaryl groups are indolyl, quinolinyl,thianaphthenyl and benzofurazanyl. N-oxides of nitrogen-containingheteroaryl groups are also included. All positional isomers arecontemplated, e.g., 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.R⁴-heteroaryl refers to such groups wherein substitutable ring carbonatoms have an R⁴ substituent.

[0058] Where R² and R³, or R⁶ and R⁷ substituents on a nitrogen atomform a ring and additional heteroatoms are present, the rings do notinclude adjacent oxygen and/or sulfur atoms or three adjacenthetero-atoms. Typical rings so formed are morpholinyl, piperazinyl andpiperidinyl.

[0059] In the above definitions, wherein variables R⁶, R⁷, R⁸, R¹³, R¹⁴,R¹⁵, R³⁰, R³¹ and R³², for example, are said to be independentlyselected from a group of substituents, we mean that R⁶, R⁷, R⁸, R¹³,R¹⁴, R¹⁵, R³⁰, R³¹ and R³² are independently selected, but also thatwhere an R⁶, R⁷, R⁸, R¹³ R¹⁴, R¹⁵, R³⁰ R³¹ or R³² variable occurs morethan once in a molecule, those occurrences are independently selected(e.g., if R is —OR⁶ wherein R⁶ is hydrogen, X can be —N(R⁶)— wherein R⁶is ethyl). Similarly, R⁴ and R⁵ can be independently selected from agroup of substituents, and where more than one R⁴ and R⁵ are present,the substituents are independently selected; those skilled in the artwill recognize that the size and nature of the substituent(s) willaffect the number of substituents which can be present.

[0060] Compounds of formula I can have at least one asymmetrical carbonatom and all isomers, including diastereomers, enantiomers androtational isomers, as well as E and Z isomers of the oxime, hydrazoneand olefin groups, are contemplated as being part of this invention. Theinvention includes d and I isomers in both pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, either by reacting optically pure or optically enrichedstarting materials or by separating isomers of a compound of formula I.

[0061] Those skilled in the art will appreciate that for some compoundsof formula I , one isomer will show greater pharmacological activitythan other isomers.

[0062] Compounds of the invention have at least one amino group whichcan form pharmaceutically acceptable salts with organic and inorganicacids. Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, tartaric, succinic, ascorbic, maleic, methanesulfonic and othermineral and carboxylic acids well known to those in the art. The salt isprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt. The free base form may beregenerated by treating the salt with a suitable dilute aqueous basesolution such as dilute aqueous sodium bicarbonate. The free base formdiffers from its respective salt form somewhat in certain physicalproperties, such as solubility in polar solvents, but the salt isotherwise equivalent to its respective free base forms for purposes ofthe invention,

[0063] Certain compounds of the invention are acidic (e.g., thosecompounds which possess a carboxyl group). These compounds formpharmaceutically acceptable salts with inorganic and organic bases.Examples of such salts are the sodium, potassium, calcium, aluminum,gold and silver salts. Also included are salts formed withpharmaceutically acceptable amines such as ammonia, alkyl amines,hydroxyalkylamines, N-methylglucamine and the like.

[0064] Compounds of formula I can be prepared using methods well knownto those skilled in the art, for example by procedures disclosed in U.S.Pat. No. 5,696,267, incorporated herein by reference. The skilledartisan will recognize that other procedures may be applicable, and thatthe procedure may be suitably modified to prepare other compounds withinthe scope of formula I.

[0065] Compounds of formula I as defined are preferably prepared asshown in the following reaction scheme as disclosed in U.S. Pat. No.5,696,267. In the reaction scheme, the variables are as defined above:

[0066] In step 1, a compound of formula 47A, wherein Q is as definedabove, is reacted with a base such as lithium diisopropylamide (LDA),KHMDS or KH in an inert organic solvent such as THF or DME to generate adianion. An acid chloride, ester or amide of formula 46A, 46B, or 46C isadded to give a ketone of formula 48. Preferable reaction temperaturesranges from −78° C. to 30° C.

[0067] Alternatively, compounds of formula 48 can be generated by thereaction of a compound of formula 46, preferably 46C, with a metallatedspecies of formula QCH₂Mt where Mt is a metal, such as lithium or MgHal,wherein “Hal” is halogen. The metallated species QCH₂Mt can be generatedby conventional procedures, such as treatment compounds of formulaQCH₂Hal with Mg or by treating QCH₃ with an organolithium base.

[0068] In step 2, for compounds wherein R is not hydrogen, the ketone 48is reacted with a suitable base, such as LDA or KH in an inert organicsolvent such as THF. For compounds wherein R is alkyl or hydroxyalkyl, acompound R—R¹⁷″, wherein R17″ is leaving group such as Br, I or triflateis added. For compounds wherein R is OH, an appropriate oxidizing agentsuch as dimethyldioxirane or Davis reagent is added. Preferable reactiontemperatures range from −78° to 50° C. For compounds of the presentinvention wherein R is H, the ketone 48 is used directly in Step 3.

[0069] In step 3, ketone 49 is reacted with a base such as LDA in asolvent such as THF, then an olefin of formula 50 is added, wherein R¹⁷″is as defined above, to give the adduct 51. Preferable reactiontemperatures range from −78° C. to 60° C.

[0070] In step 4, ketone 51 is reacted with HA′, wherein A′ is NH—OR¹,in an organic solvent such as pyridine or ethanol at a temperature from25° C. to 150° C. to give a compound of formula 52.

[0071] In step 5, a compound of formula 52 is oxidized by ozonolysis togive an aldehyde of formula 53. Suitable organic solvents include EtOAc,CH₃OH, ethanol, CH₂Cl₂ or the like. Preferable reaction temperatures arefrom −78 to 0° C.

[0072] In step 6, an aldehyde of formula 53 is reacted with a compoundof formula Z-H, wherein Z is as defined above. The reaction ispreferably carried out with a suitably substituted amine (as its acidsalt e.g. HCl or maleate or as its free base) and a hydride source suchas NaBH₃CN or sodium triacetoxyborohydride in a suitable solvent (e.g.CH₃OH, CH₃CH₂OH, or CF₃CH₂OH for NaBH₃CN, or THF, 1 ,2-dichloroethane,CH₃CN or CF₃CH₂OH for triacetoxyborohydride), with 3A sieves to obtainthe desired product. Any suitable temperature can be used withpreferable temperatures between 0° C. and 25° C.

[0073] Alternatively, a compound of formula I can be prepared from 51 bythe following reaction scheme, wherein the variables are as defined forthe cited U.S. patent:

[0074] Compound 51 is oxidized to a compound of formula 54 underconditions similar to those described for step 5 above. The aldehyde offormula 54 is reacted with a compound of formula Z-H in a manner similarto that described in Step 6, and the resultant ketone is then reactedwith a compound of the formula HA′ as described above in Step 4 toobtain the compound of formula I.

[0075] Starting “ZH” groups are known or are made by procedures known inthe art. See, for example, the following Preparations 3-12.

[0076] Reactive groups not involved in the above processes can beprotected during the reactions with conventional protecting groups whichcan be removed by standard procedures after the reaction. The followingTable 1 shows some typical protecting groups: TABLE 1 Group to be Groupto be Protected and Protected Protecting Group —COOH —COOalkyl,—COObenzyl, —COOphenyl

—NH₂

—OH —OCH₃, —OCH₂OCH₃, —OSi(CH₃)_(3,)

or —OCH₂phenyl

[0077] For preparing pharmaceutical compositions from the compoundsdescribed by this invention, inert, pharmaceutically acceptable carrierscan be either solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0078] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0079] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

[0080] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

[0081] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions can take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as are conventional in the art forthis purpose.

[0082] Preferably the compound is administered orally.

[0083] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active component,e.g., an effective amount to achieve the desired purpose.

[0084] The quantity of active compound in a unit dose of preparation fortreatment of asthma, cough, bronchospasm, inflammatory diseases,migraine, nociception, depression, emesis and gastrointestinal disordersmay be varied or adjusted from about 1 mg to about 1500 mg, preferablyfrom about 50 mg to about 500 mg, more preferably from about 20 mg toabout 200 mg, according to the particular application.

[0085] The actual dosage employed may be varied depending upon therequirements of the patient and the severity of the condition beingtreated. Determination of the proper dosage regimen for a particularsituation is within the skill of the art. For convenience, the totaldaily dosage may be divided and administered in portions during the dayas required.

[0086] The amount and frequency of administration of the compounds ofthe invention and/or the pharmaceutically acceptable salts thereof willbe regulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 1500 mg/day, in two to four divided doses.

[0087] Following are examples of preparing starting materials andcompounds of formula I. As used herein, Me is methyl, Bu is butyl, Br isbromo, Ac is acetyl, Et is ethyl and Ph is phenyl.

[0088] Prepared using methods described in U.S. Pat. No. 5,696,267.

[0089] Prepared using methods described in U.S. Pat. No. 5,696,267.

[0090] Step 1: Treat a solution of 1-benzyl-4-amino piperidine (25 g,0.13 mol) in CH₃OH (5 mL) with acrylonitrile (9.6 mL, 0.15 mol) at 23°C. Stir for 22 h, and concentrate to yield the crude product.

[0091] Step 2: Dissolve the product of Step 1 (31.9 g, 0.13 mol) inCH₃OH (1 L) add cobalt (II) chloride (34 g, 0.26 mol) followed by NaBH₄(50 g, 0.13 mol) in several small portion over 45 min at 0° C. Allow theresulting suspension to stir for 1.5 h, carefully acidify with 3 N HCluntil the color turns pink. Extract the aqueous solution with ether(Et₂O) (1 L), add NaOH at 10° C. until pH=12. Extract the resultingsuspension with Et₂O (1 L), then CH₂Cl₂ (2×1 L). Filter the aqueouslayer to remove the solid material, and further extract with CH₂Cl₂ (3×1L). Concentrate the combined organic layer to give 23.6 g of the desiredproduct.

[0092] Step 3: Dissolve the product of Step 2 (10.0 g, 0.41 mol) inanhydrous tetrahydrofuran (THF) (70 mL), treat with carbonyidiimidazole(13.2 g, 0.81 mol), and heat to 60° C. for 14 h. Concentrate themixture, and filter through a silica plug with CH₂Cl₂ and CH₃OH (sat.with NH₃) at a ratio of 94:6 to give 8.6 g of the title product.

[0093] Step 1: Treat a solution of 4-amino-N-benzyl piperidine (20.4 mL,0.10 mol) in CHCl₃ (30 mL) with phthalide anhydride (10.0 g, 0.068 mol)and heat the mixture to reflux at 70° C. for 18 h. Add water and CH₂Cl₂,separate the layers, extract the aqueous layer with CH₂Cl₂ (2×40 mL),wash the combined organic layers with brine, concentrate and purify themixture with column chromatography, eluting with CH₂Cl₂ and CH₃OH (sat.with NH₃) at a ratio of 99:1 to give 6.9 g of the desired product.

[0094] Step 2: Dissolve the product of Step 1 in acetic acid (HOAc) (10mL), add zinc dust (1.28 g, 20 mmol) and heat to reflux at 120° C. for12 h. After cooling the mixture, slowly add NaHCO₃ (sat.) solution untilpH=10, separate the layers, extract the aqueous layer with CH₂Cl₂ (2×40mL), wash the combined organic layers with brine, concentrate themixture, and purify by column chromatography, eluting with EtOAc:hexane(1:1) with 2% triethylamine (TEA) to give 0.50 g product.

[0095] Treat a solution of 4-amino-N-benzyl piperidine (1.0 g, 5.26mmol) and 2-acetylbenzoic acid (1.0 g, 6.10 mmol) in dichloroethane (10mL) with NaBH₃CN (0.37 g, 6.0 mmol) and stir at 23° C. for 24 h. Heatthe mixture to 80° C. for an additional 24 h. Add water (30 mL) andEtOAc (30 mL), filter through celite, separate layers of filtrate andconcentrate the organic layer. Purify by column chromatography, elutingwith EtOAc:hexane (1:2) with 2% TEA to give 0.86 g product.

[0096] Dissolve the product of Preparation 4, Step 1 (0.76 g, 2.38 mmol)in anhydous THF (6 mL) and add CH₃MgBr (3 M, 2 mL, 6 mmol) at 0° C. Warmthe mixture and stir at 23° C. for 3 h. Quench with water and CH₂Cl₂ at0° C., separate the layers, and extract the aqueous layer with CH₂Cl₂(2×40 mL), wash the combined organic layer with brine and concentrate togive 0.68 g product.

[0097] Using procedures known in the art, treat a solution of3,4-dichloro-phenylacetic acid with N-t-BOC-sarcosine methyl ester andseparately treat 2-bromo-ethanol with t-butyldimethylsilylchloride.React the product of the first step with NaH, and add the product of thesecond step and Nal. Treat the resultant product with O-methoxylamineHCl, followed by deprotection using HCl in CH₂Cl₂. Chiral material wasobtained by chiral separation using HPLC.

[0098] Step 1: Treat a solution of t-butyl-n-(2-aminoethyl)carbamate(18.6 g, 116 mmol) and 1-benzyl-4-piperidone (20 g, 106 mmol) in CH₂Cl₂(300 mL) with HOAc (4.1 g, 68 mmol) and sodium triacetoxyborohydride (25g, 118 mmol) at 0° C., and stir for an additional 15 h at 23° C. AddNaHCO₃ (sat.) (150 mL) and extract with CH₂Cl₂ (150 mL×2), wash thecombined organic layer with brine and concentrate to give 35.5 gproduct.

[0099] Step 2: Dissolve the product of Step 1 (7 g, 21 mmol) and Et₃N(6.37 g, 63 mmol) in CH₂Cl₂ (200 mL), add chloroacetyl chloride (2.85 g,25 mmol), and stir for 2 h at 23° C. Add NaHCO₃ solution (150 mL) andextract with CH₂Cl₂ (150 mL×2), wash the combined organic layer withbrine and concentrate. Purify by column chromatography, eluting withCH₂Cl₂ and CH₃ OH (sat. with NH ₃) at a ratio of 97:3 to give 5.3 gproduct.

[0100] Step 3: Dissolve the product of Step 2 (5.3 g, 12.0 mmol) inCH₂Cl₂ with trifluoroacetic acid (15 mL) and stir for 1 h at 23° C.Remove the solvent under reduced pressure and dilute with CH₂Cl₂ andNaOH (1 M) until pH=10. Extract with CH₂Cl₂ (150 mL×2), wash thecombined organic layer with brine, and concentrate to yield 3.3 g of thetitle compound.

[0101] Step 1: Use a procedure similar to Step 1 of Preparation 8,substituting glycine methyl ester hydrochloride fort-butyl-n-(2-aminoethyl)carbamate and HOAc.

[0102] Step 2: Treat the product of Step 1 with Boc-glycine using anamidation procedure similar to Step 1 of Example 7A.

[0103] Step 3: Treat the product of Step 2 with trifluoroacetic acidusing a procedure similar to Step 3 of Preparation 8 to obtain the titlecompound.

[0104] Step 1: Dissolve 4-benzyl-piperidone (11.48 g, 50.7 mmol) in EtOH(60 mL), treat with 3-aminopropanol (8.29 g, 110.4 mmol) and stir for 90min. Cool to 0° C. and add HCl in dioxane (14 mL, 56 mmol), followed byNaBH₃CN (7.8 g, 124 nmol). Allow the mixture to warm up to 23° C., andstir for additional 20 h. Quench with water and dilute with EtOAc,separate the organic layer and basify the aqueous layer until pH>10.Extract the organic layer with EtOAc (2×100 mL), wash the combinedorganic layer with brine and concentrate. Purify by columnchromatography, eluting with CH₂Cl₂ and CH₃OH (sat. with NH₃) at a ratioof 94:6 to give 7.5 g product.

[0105] Step 2: Treat the product of step 1 using procedure similar toPreparation 3, Step 3, to give 6.6 g of the title compound.

[0106] To a 5 L 3-neck flask equipped with a mechanical stirringapparatus and charged with 1,2 dichloroethane (400 mL), addN-Boc-piperidone (20 g, 100 mmol, 1 eq) followed by 3-amino-1-propanol(9.21 mL, 120 mmol, 1.2 eq) and stir for 30 min. Add Na(OAc)₃BH (25.4 g,120 mmol, 1.2 eq) and stir for 4 h. Cool reaction to 0° C. and add 300mL of saturated aqueous NaHCO₃. Add p-nitrophenylchloroformate (30.25g,150 mmol, 1.5 eq), stir for 90 min and store for 14 h at −20° C. Warm to0° C. and check for complete reaction by TLC. Prepare a solution of NaBr(11.3 g, 110 mmol, 1.1 eq in 300 mL of saturated aqueous NaHCO₃(sonicate for 5 min)) and add to the reaction vessel. Add TEMPO (156 mg,1 mmol). With vigorous stirring, use a 500 mL addition funnel to add 300mL of commercial bleach (ca 0.7 M, 220 mmol, 2.2 eq). If reaction is notcomplete as shown by TLC, add bleach in small portions (25 mL) untilcomplete. When TLC shows complete reaction, add saturated aqueousNa₂S₂O₃ (300 mL) and transfer to a separatory funnel. Isolate theorganic layer and extract the aqueous layer with CH₂Cl₂ (2×1 L). Combinethe organic layers and wash with saturated aqueous NaHCO₃ (1 L). Backextract the last aqueous wash with 1 L CH₂Cl₂, dry over Na₂SO₄ andconcentrate to give 65 g crude product. Purify by silica gelchromatography using 800 g silica, eluting with hexane/EtOAc gradientelution (2:1→1:1) to obtain 36.5 g (87%) of the desired aldehyde.Preparations 12A-12O

Prep. no. R²⁶ 12A CH₃ 12B (CH₃)₂CH 12C

12D

12E

12F

12G

12H

12I

12J

12K

12L

12M

12N OH 12O

12P

12Q

12R

12S

12T

12U

[0107] Preparation 12A

[0108] Step 1: Using a procedure similar to Preparation 11 with phenylchloroformate in place of 4-nitrophenylchloroformate, prepare thecorresponding phenyl carbamate aldehyde.

[0109] Step 2: Stir a solution of the product of step 1 (5 g, 13.2mmol), NH₂CH₃ (7.3 mL of 2 M in THF), in 2,2,2-trifluoroethanol (150 mL)for 30 min, then add 4.67 g of Na(OAc)₃BH and stir for 18 h. Filterthrough a frit, rinse with EtOAc, wash the filtrate with sat NaHCO₃ thenbrine, dry with Na₂SO4 and concentrate in vacuo. Dissolve the crude inDMF (100 mL) and heat to 100° C. for 1 h. Remove the DMF in vacuo andpurify by silica gel chromatography, eluting with EtOAc/CH₃OH 9:1 toobtain 2.46 g of the desired boc-piperidine.

[0110] Step 3: Dissolve the product of step 2 in 30 mL of CH₂Cl₂ (30 mL)at 0° C. and treat with 50 mL of HCl/dioxane (4N) and stir until nostarting material remains by TLC . Concentrate in vacuo and filter theresulting HCl salt through a plug of silica gel, eluting withCH₂Cl₂/CH₃OH (sat with NH₃) to obtain the desired piperidine free base.

[0111] Preparation 12B

[0112] Using a procedure similar to Preparation 12A, substituteisopropylamine for NH₂CH₃ and heat to 125° C. for 6-8 h instead of 100°C. for 1 h in step 2.

[0113] Preparation 12C-12H

[0114] Step 1: Using a procedure similar to that of Preparation 12A,substituting the product of Preparation 11 for the phenyl carbamate instep 1 and using the appropriate amine, the correspondingBoc-piperidines were prepared. For insoluble amines (Prep. 12D) 1-20%Et₃N was added to 2,2,2 trifluoroethanol as a co-solvent in step 2. Instep 2, hindered amines (Prep. 12H) may require sustained heating (120°C., 4-5d) in DMF for cyclization to occur. For less hindered amines,cyclization may be spontaneous and may not require heating in DMF.

[0115] Step 2: Deprotect, using a procedure similar to Preparation 12A,step 3.

[0116] Preparation 12I-12L

[0117] Treat a solution (0.05-0.25 mmol) of the desired Boc protectedpiperidine obtained from Preparation 12E-12H, step 1, in CH₂Cl₂ with1.5-5 eq mCPBA and stir for 2-18 h. Concentrate in vacuo and purify bysilica gel chromatography. Deprotect the Boc group using a proceduresimilar to that of Preparation 12A, step 3, to give the appropriatepiperidine.

[0118] Preparation 12M

[0119] Using a procedure similar to Preparations 12C-H, steps 1 and 2,substituting glycineamide for the appropriate amine, the resultingglycineamide substituted urea / piperidine free base is prepared.

[0120] Preparation 12N

[0121] Step 1: Treat a solution of the product of Preparation 12A, step1 (6.2 g, 16.5 mmol) in pyridine (100 mL) with NH₂OH (1.72 g, 24.7 mmol)and heat to 60° C. for 2.5 h. Cool and concentrate in vacuo and purifyby silica gel chromatography, eluting with CH₂Cl₂/CH₃OH (NH₃) to obtain5.9 g (88%) of the oxime as a white powder.

[0122] Step 2: Treat a solution of the product of step 1 (5.7 g, 15mmol) in 170 mL CH₃OH with a trace amount of methyl orange indicatorfollowed by NaCNBH₃ (1.03 g). Add 1 M HCl/CH₃OH until mixture remainsorange (ca. 23 mL). Quench with 400 mL EtOAc and 75 mL sat NaHCO₃.Filter the resulting emulsion through celite and wash with EtOAc. Washorganic layers with 75 mL saturated NaHCO₃, then brine, dry over Na₂SO₄and concentrate in vacuo to obtain 3.82 g (67%) of the hydroxyl amine asa colorless glass.

[0123] Step 3: Dissolve the product of step 2 in 50 mL DMF and heat to100° C. for 4 h. Concentrate in vacuo and purify by silica gelchromatography using CH₂Cl₂/ CH₃OH (NH₃) to obtain 3.0 g (99%) of thehydroxyl urea.

[0124] Step 4: In a procedure similar to Preparation 12A, step 3,deprotect the Boc group to obtain the desired piperidine.

[0125] Preparation 12O

[0126] Step 1: Treat a solution of the product of Preparation 12A, step1 (3.0 g, 7.13 mmol) in 1,2-dichloroethane (20 mL) with aminomorpholine(1.37 mL, 14.25 mmol) and Na(OAc)₃BH (3.0 g). Isolate the resultinghydrazone by filtering the reaction mixture through a frit andconcentrating in vacuo.

[0127] Step 2: Treat a solution of the product of step 1 in 50 mL THFwith 1 eq of tosic acid followed by NaCNBH₃ (2 eq). Quench with sat.NaHCO₃ and extract with EtOAc. Wash the organic layers with saturatedNaHCO₃, then brine, dry over Na₂SO₄ and concentrate in vacuo. Purify bysilica gel chromatography, eluting with EtOAc/hexane (2:1) with 2% Et₃Nto obtain 1.5 g of the desired hydrazone.

[0128] Step 3: Dissolve the product of step 2 in 50 mL DMF and heat to120° C for 3 h. Concentrate in vacuo and purify by silica gelchromatography, eluting with CH₂Cl2/CH₃OH (NH₃) to obtain 255 mg (10%, 2steps) of the aminomorpholino urea.

[0129] Step 4: In a procedure similar to Preparation 12A, step 3,deprotect the Boc group to obtain the desired piperidine.

[0130] Preparation 12P

[0131] Step 1: Using a procedure similar to Preparation 12A, Step 2,substitute aminoacetonitrile for methyl amine. Dissolve the product inCH₃OH, add Raney Ni, and shake the resulting mixture on a Parr shaker at50 psi of H₂ pressure for 3 h. Filter the mixture through celite andconcentrate to give the desired product.

[0132] Step 2: Dissolve the product of Step 1 (0.17 g, 0.52 mmol) inCH₂Cl₂ and treat with methyl isocyanate (0.035 ml, 0.57 mmol) at 23° C.for 3 h. Dilute with water and CH₂Cl₂, separate the layers, and extractthe aqueous layer with CH₂Cl₂ (2×40 ml), wash the combined organiclayers with brine and concentrate. Purify by column chromatography usingCH₂Cl₂ and CH₃OH (sat. with ammonia) at a ratio of 98:2 to give 0.68 gof product.

[0133] Step 3: Use a procedure similar to Preparation 12A, Step 3, togive the desired product.

[0134] Preparation 12Q-12T

[0135] Using a procedure similar to Preparation 12B, substitute formethyl isocyanate the appropriate isocyante or chloride.

[0136] Preparation 12U

[0137] Step 1: Dissolve the product form Preparation 12P, Step 1, indioxane, treat with sulfamide, reflux at 100° C. for 8 h, andconcentrate to give a crude product.

[0138] Step 2: Use a procedure similar to Preparation 12A, Step 3, togive the desired product.

EXAMPLE 1

[0139]

[0140] Step 1: Dissolve product of Preparation 3 (11.3 g, 0.042 mol) inanhydrous dimethylformamide (DMF) (30 mL), treat it with lithiumbis(trimethylsilyl)amide (1 M, 50 mL, 0.050 mol) at 0° C., allow thereaction mixture to warm up to 23° C. over 40 min. Add t-butylbromoacetate (13.5 mL, 0.084 mol), and stir for 18 h. Quench with waterand dilute with ethyl acetate (EtOAc), separate the organic layer,concentrate and purify the mixture by column chromatography eluting withCH₂Cl₂ and CH₃OH (sat. with NH₃) at a ratio of 98:2 to give 12.1 gproduct.

[0141] Step 2: Bubble HCl into a solution of the product of Step 1 (12.2g, 0.032 mol) in CH₃OH (200 mL) for 15 min at 0° C. and heat theresulting solution at 60° C. for 2 h. After cooling, pour the reactionmixture into 10% aqueous NaOH solution (100 mL) and add NaHCO₃ solution(sat.) until pH=10. Separate the organic layer and further extract theaqueous layer with CH₂Cl₂ (2×100 mL), wash the combined organic layerwith brine and concentrate to yield 12.3 g product.

[0142] Step 3A: Dissolve the product of Step 2 (1 g, 3.0 mmol) in CH₃OH(10 mL) add Pd(OH)2 on carbon (150 mg), and shake the resulting mixtureon a Parr shaker at 50 psi of H₂ pressure for 3 h. Filter the mixturethrough celite and concentrate to give a crude product. Re-dissolve theproduct and the aldehyde from Preparation 1 (1.5 g, 3.14 mmol) intrifluoroethanol (10 mL), treat with 3Åmolecular sieves (0.3 g) andNaBH₃CN (0.37 g, 6.0 mmol), and stir for 2 h. Add water (30 mL) andEtOAc (30 mL), filter the mixture through celite, separate layers offiltrate, extract the aqueous solution with EtOAc ( 2×40 mL), andconcentrate the combined organic layer. Purify by column chromatography,eluting with CH₂Cl₂ and CH₃OH (sat. with NH₃) at a ratio of 98:2 to give0.89 g of desired product. HRMS (FAB, M+H⁺): Calc'd: 714.1784, found:714.1791.

[0143] Step 3B: Alternatively, to prepare optically active material,proceed in a similar manner as Step 3A using the aldehyde fromPreparation 2 in place of the aldehyde from Preparation 1,dichloroethane in place of trifluoroethanol, and sodiumtriacetoxyborohydride in place of NaBH₃CN. HRMS (FAB, M+H⁺): Calc'd:714.1784, found: 714.1779.

EXAMPLE 2

[0144]

[0145] Step 1: Using a procedure similar to Preparations 12C-H, steps 1and 2, and substituting serine methyl esters·HCl for the appropriateamine, the resulting serine methyl ester substituted urea / piperidinefree base is prepared.

[0146] Step 2: Treat the product of step 1 (3.68 mmol) in 1,2dichloroethane (20 mL and 5 mL CF₃CH₂OH) with Preparation 2 (1.23 g,2.45 mmol) and 3Å MS (1.5 g). Stir for 30 min, then add Na(OAc)₃BH (943mg, 4.5 mmol) and stir for 1-5 h. Filter through celite and wash thecelite pad with EtOAc. Transfer to a separatory funnel and wash with satNaHCO₃ (2×50 mL) then brine, dry the organic layer with Na₂SO₄ andconcentrate in vacuo. Purify by chromatography (EtOAc/NEt₃) to obtain1.3 g of the desired product.

EXAMPLE 3

[0147]

[0148] Use a procedure similar to Example 2, substituting tyrosine ethylesters·HCl for serine methyl esters·HCl to obtain the product.

EXAMPLE 4

[0149]

Ex. R²⁶ HRMS (FAB, M + H⁺) 4A

Calc'd: 700.1627, found: 700.1619 4B

Calc'd: 753.2256 found: 753.2248 4C

Calc'd: 727.2100, found: 727.2120 4D

Calc'd: 713.1943, found: 713.1937 4E

Calc'd: 699.1787, found: 699.1784 4F

Calc'd: 769.2206, found: 769.2207 4G

Calc'd: 782.2522, found: 782.2514 4H

n = 1 Calc'd: 785.1977, found: 785.1974 n = 2 Calc'd: 817.1875, found:817.1862 41

Calc'd: 782.1617 found: 782.1624 4J

Calc'd: 783.1569 found: 783.1570 4K

Calc'd: 728.1940 found: 728.1930 4L

Calc'd: 782.1657 found: 782.1662 4M

Calc'd: 771.2362 found: 771.2350 4N

Calc'd: 790.2097 found: 790.2103 4O

Calc'd: 740.1940 found: 740.1943 4P

Calc'd: 742.2097 found: 742.2091 4Q

Calc'd: 768.2253 found: 768.2235 4R

Calc'd: 784.2202 found: 784.2198 4S

Calc'd: 758.1868 found: 782.1862 4T

Calc'd: 806.1868 found: 806.1853 4U

Calc'd: 784.2025 found: 784.2022 4V

Calc'd: 728.1940, found: 728.1932 4W

Calc'd: 714.1784, found: 714.1776 4X

Calc'd: 741.2256, found: 741.2247 4Y

Calc'd: 686.1834 found: 686.1855 4Z

Calc'd: 700.1991 found: 700.1984 4ZZ

Calc'd: 776.2304 found: 776.2302

[0150] Example 4A:

[0151] Dissolve the product of Step 3A of Example 1 (0.50 g, 0.69 mmol)in CH₃OH (6 mL), add a solution of NaOH (60 mg, 1.5 mmol) in water (0.25mL), and stir for 4 h. Add an equivalent of HCl (10% in water) andextract the mixture with 15% CH₃OH in CH₂Cl₂ (5×30 mL). Concentrate thecombined organic layer and purify by column chromatography using 15%CH₃OH in CH₂Cl₂ to give 0.36 g of the desired product.

[0152] Example 4B:

[0153] Dissolve the product of Example 4A (60 mg, 0.086 mmol) andcarbonyldiimidazole (28 mg, 0.17 mmol) in CH₂Cl₂ (1 mL), and addpyrrolidine (22 mL, 0.26 mmol) at 0° C. After stirring at 23° C. for 12h, add water (20 mL) and CH₂Cl₂ (20 mL), separate the layers, extractthe aqueous layer with CH₂Cl₂ (2×20 mL), wash the combined organic layerwith brine, concentrate, and purify the mixture with columnchromatography eluting with CH₂Cl₂ and CH₃OH with NH₃ (98:2) to give 47mg of the product.

[0154] Examples 4C-4J:

[0155] Prepare the compounds by reacting the product of Example 4A withan appropriate amine according to procedure similar to Example 4B.

[0156] Example 4K:

[0157] Dissolve the product of Example 4A (200 mg, 0.29 mmol),1,3-dicyclohexylcarbodiimide (DCC) (87 mg, 0.43 mmol) and4-dimethyl-aminopyridine (DMAP) (53 mg, 0.43 mmol) in CH₂Cl₂ (2 mL), addEtOH (25 mL, 0.43 mmol) at 0° C. After stirring at 23° C. for 12 h, addwater (20 mL) and CH₂Cl₂ (20 mL), separate the layers, extract theaqueous layer with CH₂Cl₂ (2×20 mL), wash the combined organic layerwith brine, concentrate and purify the mixture with columnchromatography eluting with CH₂Cl₂ and CH₃OH with NH₃ (97 :3) to give165 mg of the product.

[0158] Examples 4L-4R:

[0159] Prepare the target compounds by reacting the product of Example4A with an appropriate alcohol according to a procedure similar toExample 4K.

[0160] Example 4S-4T:

[0161] Prepare the compounds using a procedure similar to Example 4K,using bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), Et₃N andappropriate thiols in place of DCC, DMAP and EtOH.

[0162] Example 4V:

[0163] Use a procedure similar to Example 1, Step 1, using methyl3-bromopropionate in place of t-butyl bromoacetate, followed bydebenzylation and reductive amination using a procedure similar toExample 1, Step 3.

[0164] Example 4W:

[0165] Treat the product of Example 4Y using a hydrolysis proceduresimilar to that of Example 4A.

[0166] Example 4X:

[0167] Treat the product of Example 4W using an amidation proceduresimilar to Example 4B using (CH₃)₂NH in place of pyrrolidine.

[0168] Example 4Y:

[0169] 1 ) Dissolve the product of Preparation 11 (19 g, 44 mmol) andethanol-amine (4 mL, 66 mmol) in dichloroethane (120 mL) and stir for 30min. Treat with sodium triacetoxyborohydride (14 g, 66 mmol) and stirfor 14 h. Add NaHCO₃ (sat.) (150 mL), extract with CH₂Cl₂ (150 mL×2),wash the combined organic layer with brine and concentrate to give 8.75g product.

[0170] 2) Treat the product of Step 1 by a procedure similar to Example1, Step 3A, to give the product.

[0171] Example 4Z:

[0172] Dissolve the product of Example 4Y (138 mg, 0.2 mmol) in dry THF(1 mL), add NaH (16 mg, 0.4 mmol) at 0° C. and stir for 15 min. Add CH₃l(19 mL, 0.3 mmol) at 0° C., allow the mixture to warm to 23° C., andstir for 2 h. Quench the reaction at 0° C. with water (10 mL) and dilutewith EtOAc (10 mL). Separate the layers, extract aqueous solution withEtOAc (2×40 mL) and concentrate the combined organic layer. Purify bycolumn chromatography using EtOAc and CH₃OH (99:1) with 5% Et₃N to give103 mg product.

[0173] Example 4ZZ:

[0174] Treat the product of Example 4Y using a procedure similar toExample 4Z substituting benzyl bromide for CH₃1.

EXAMPLE 5

[0175]

Ex. Z HRMS (FAB, M + H⁺) 5A

Calc'd: 675.1463, found: 675.1459 5B

Calc'd: 689.1620, found: 689.1618 5C

Calc'd: 705.1569, found: 705.1565

[0176] Example 5A-5C

[0177] Prepare the Compounds by a procedure similar to Example 1, Step3, using the products of Preparations 4, 5 and 6, respectively.

EXAMPLE 6

[0178]

HRMS (FAB, M + H⁺) (unless otherwise Ex. R²⁶ specified) 6A

Calc'd: 700.1627, found: 700.1619 6B

Calc'd: 753.2256, found: 753.2254 6C

Calc'd: 727.2100, found: 727.2105 6D

Calc'd: 713.1943, found: 713.1941 6E

Calc'd: 769.2206, found: 769.2204 6F

Calc'd: 699.1791, found: 699.1787 6G

Calc'd: 785.1977, found: 785.1987 6H

Calc'd: 728.1940 found: 728.1942 6I

Calc'd: 686.1834 found: 686.1846 6J

Calc'd: 716.1754 found: 716.1744 6K

Calc'd: 714.2147 found: 714.2143 6L

Calc'd: 742.2097 found: 742.2081 6M

Calc'd: 728.1940 found: 728.1930 6N

Calc'd: 729.2070 found: 785.2061 6O H Calc'd: 642.1572, found: 642.15706P CH₃ LRMS: (M + H⁺) 657.9 6Q (CH₃)₂CH— LRMS: (M + H⁺) 687.0 6R

Calc'd: 722.1834, found: 722.1832 6S

Calc'd: 724.1852, found: 724.1879 6T

LRMS: (M + H⁺) 735.2 6U

LRMS: (M + H⁺) 735.2 6V

LRMS: (M + H⁺) 735.2 6W

Calc'd: 719.1838, found: 719.1849 6X

LRMS: (M + H⁺) 751.2 6Y

Calc'd: 749.1943, found: 749.1922 6Z

Calc'd: 749.1943, found: 749.1937 6AA

Calc'd: 735.1787, found: 735.1800 6BB

Calc'd: 730.1733, found: 730.1733 6CC

Calc'd: 806.2046, found: 806.2034 6DD

LRMS: (M + H⁺) 731.1 6EE

LRMS: (M + H⁺) 807.2 6FF

Calc'd: 699.1787, found: 699.1791 6GG

Calc'd: 714.1898, found: 714.1891 6HH

Calc'd: 698.1967, found: 698.1959 6II OH Calc'd: 660.1492, found:660.1487 6JJ

LRMS: (M + H⁺) 660.2 6KK

LRMS: (M + H⁺) 717.2 6LL

Calc'd: 727.2100, found: 727.2114 6MM

Calc'd: 742.2209, found: 742.2199 6NN

LRMS: (M + H⁺) 730 6OO

LRMS: (M + H⁺) 800 6PP

Calc'd: 729.2070, found: 729.2052 6QQ

Calc'd: 765.1740, found: 765.1747 6RR

Calc'd: 766.1693, found: 766.1685

[0179] Example 6A:

[0180] Prepare the compound by a procedure similar to Example 4A usingproduct of Example 1, Step 3B in place of the product of Example 1,Step3A.

[0181] Example 6B-6G:

[0182] Treat the product of Example 6A with appropriate amines using anamidation procedure similar to Example 4B using1-(3-dimethylamino-propy- 3-ethylcarbodiimide (EDC) and1-hydroxybenzotriazole (HOBt) in place of carbonyidiimidazole.

[0183] Example 6H-6J:

[0184] Prepare the compounds by procedures similar to Examples 4K, 4Yand 4W, except using the optically pure product from Preparation 2 inplace of product of Preparation 1.

[0185] Example 6K:

[0186] Dissolve the product of Example 6H (0.12 g, 0.16 mmol) inanhydous THF (2 mL) and add CH₃MgBr (3 M, 0.2 mL, 0.6 mmol) at 0° C.Warm the mixture and stir at 23° C. for 3 h. Add water and CH₂Cl₂ at 0°C., separate the layers, extract the aqueous layer with CH₂Cl₂ (2×40mL), wash the combined organic layer with brine and concentrate. Purifyby column chromatography eluting with CH₂Cl₂ and CH₃OH (99:1 to 95:5) togive 0.05 g of the product.

[0187] Example 6L:

[0188] Step 1: Use the procedure in Preparation 11, substitutingN-benzyl piperidone for N-Boc-piperidone, and substituting a standardSwern oxidation for TEMPO oxidation.

[0189] Step 2: Dissolve the product of Step 1 (6.83 g, 16.6 mmol) andα,α-dimethyl glycine methyl ester hydrochloride (2.86 g, 18.6 mmol) intrifluoroethanol (32 mL) and CH₂Cl₂ (63 mL), add NaSO₄ (2.8 g) and stirfor 30 min. Treat the mixture with sodium triacetoxy borohydride andstir for additional 4 h. Filter off the solid and concentrate to yieldthe crude product. Purify by column chromatography eluting with EtOAcand CH₃OH (99:1 to 95:5) to give 7.65 g product.

[0190] Step 3: Dissolve the product of Step 2 (1.54 g, 3 mmol) intoluene (140 mL) and heat in a sealed tube at 120° C. for 40 h. Cool andremove the solvent, re-dissolve in EtOAc and CH₂Cl₂, wash with 1 N NaOH,brine and concentrate to yield 0.97 g product.

[0191] Step 4: Treat the product in Step 3 using a procedure similar toPreparation 3, Step 3, to give the product.

[0192] Example 6M:

[0193] Step 1: Treat the product of Step 3 of Example 6L with ahydrolysis procedure similar to Example 6A, but reflux at 70° C. for 24h.

[0194] Step 2: Treat the product of Step 1 using a procedure similar toExample 1, Step 3 to give the product.

[0195] Example 6N:

[0196] Treat the product of Example 6M with an amidation proceduresimilar to Example 4E to give the product.

[0197] Example 6O:

[0198] Step 1: Dissolve the product of Preparation 3, step 3 (2.0g, 7.5mmol) in CH₃OH (50 mL) and treat with Pd(OH)₂ (20% on C, 50% H₂O)followed by H₂ (40 psi). After shaking for 17 h on Parr shaker, filterthrough celite and concentrate to obtain the desired piperidine (1.33 g,7.3 mmol, 98%).

[0199] Step 2: Treat the product of step 1 (2.13g, 4.5 mmol) in1,2-dichloroethane (15 mL) with Preparation 2 (1.42 g, 3.0 mmol) and3ÅMS (2g). Stir for 30 min and then add Na(OAc)₃BH (943 mg, 4.5 mmol)and stir for 1-5 h. Filter through celite and wash the celite pad withEtOAc. Transfer to a separatory funnel, wash with sat NaHCO₃ (2×50 mL),brine and dry the organic layer with Na₂SO₄ and concentrate in vacuo.Purify by chromatography (EtOAc/NEt₃→EtOAc/NEt₃/CH₃OH gradient) toobtain 810 mg of the desired product.

[0200] Example 6P through 6AA, 6FF, 6II, and 6LL-6RR:

[0201] Use the appropriate piperidine from Preparation 12A through 12L,12M, 12N, and 12O-12U and the aldehyde from Preparation 2 in a proceduresimilar to example 6O, step 2 to obtain the title compounds.

[0202] Example 6BB:

[0203] Use the product of Example 2 in a procedure similar to Example 4Ato obtain the corresponding carboxylic acid compound.

[0204] Example 6CC:

[0205] Use the product of Example 3 in a procedure similar to Example 4Asubstituting LiOH for NaOH and aqueous DME for CH₃OH to obtain thecorresponding carboxylic acid title compound.

[0206] Examples 6DD and 6EE:

[0207] With Examples 6BB and 6CC as the starting carboxylic acids, use aprocedure similar to Example 4K using HOBT in place of DMAP and usingNH₃ in THF as the amine to obtain Examples 6DD and 6EE, respectively.

[0208] Example 6GG:

[0209] Step 1: Cool a suspension of dry NH₄Cl (58 mg) in benzene (5 mL)to 0° C. and treat with 525 μL of 2 M trimethylaluminum in toluene. Warmto 23° C. and stir for 1 h. Add 250 mg of example 6FF and heat themixture to reflux for 2.5 h. Cool and remove the solvent in vacuo andpurify the resulting nitrile by silica gel chromatography usingCH₂Cl₂/CH₃OH (NH₃) (95:5) as the eluant to obtain 140 mg (57%) of thenitrile.

[0210] Step 2: Sonicate a mixture of NH₂OH (152 mg, 2.21 mmol) in dryEtOH (5 mL) and 1 N KOH/CH₃OH (1.76 mL) for 15 min. Add this suspensionto a solution of the product of step 1 (300 mg) in dry EtOH (7 mL) with3ÅMS and heat to reflux for 2 h. Quench with saturated NaHCO₃, dilutewith EtOAc (150 mL), filter through a frit and concentrate in vacuo.Purify by silica gel chromatography using CH₂Cl₂/CH₃OH (NH₃) (97:3→95:5)to obtain the title compound.

[0211] Example 6HH:

[0212] Treat a solution of the product of Example 6GG, step 1 (300 mg)in CH₃OH (5 mL) with 47 mg of NaOCH₃ and stir for 18 h at 23° C. Add dryNH₄Cl and stir for 4 h. Remove the solvent in vacuo and purify by silicagel chromatography using CH₂Cl₂/CH₃OH (NH₃) (95:5→80:10) to obtain 262mg (86%) of the title compound.

[0213] Example 6JJ:

[0214] Treat a solution of example 6II (250 mg, 0.38 mol) and 46 μL(0.57 mmol) of pyridine in 3 mL CH₂Cl₂ with methylisocyanate (33.5 μL,0.57 mmol) and stir for 3 h. Remove the solvent in vacuo and purify bysilica gel chromatography using CH₂Cl₂/CH₃OH (NH₃) (95:5) to obtain 226mg (83%) of the title compound.

[0215] Example 6KK:

[0216] Step 1: Treat a solution of Example 6II (500 mg, 0.76 mol) in dryDMF (10 mL) at 0° C. with NaH (46 mg, 60%) and stir for 30 min. Addmethylbromoacetate (86 μL, 0.914 mmol) stir for 30 min and quench with 3mL saturated NaHCO₃. Extract with EtOAC, filter through a frit, washwith saturated NaHCO₃, brine, dry with Na₂SO₄ and concentrate in vacuo.Purify by silica gel chromatography using CH₂Cl₂/CH₃OH (NH₃) (97:3) toobtain 440 mg (79%) of the methyl ester.

[0217] Step 2: Treat a solution of the product of step 1 (389 mg) withCH₃OH saturated with NH₃ (20 mL) and sonicate for 2 h. Concentrate invacuo. Purify by silica gel chromatography using CH₂Cl₂/CH₃OH (NH₃)(95:5) to obtain 300 mg (79%) of the title compound.

EXAMPLE 7

[0218]

Ex. E HRM (FAB, M + H⁺) 7A

Calc'd: 602.2665 found: 602.2674 7B

Calc'd: 610.2163 found: 610.2181 7C

Calc'd: 639.2020 found: 639.2006 7D

Calc'd: 710.2116 found: 710.2099 7E

Calc'd: 642.2226 found: 642.2226 7F

Calc'd: 618.2272 found: 618.2264

[0219] Example 7A:

[0220] Step 1: Dissolve the product of Preparation 7 (1.0 g, 1.36 mmol),EDC (0.38 g, 2.00 mmol) and HOBt (0.24 g, 1.8 mmol) in CH₂Cl₂ (5 mL),add 3,5-dimethyl benzoic acid (0.3 g, 2.00 mmol) and Et₃N (0.7 mL, 4.00mmol) at 0° C. After stirring at 23° C. for 12 h, add water (20 mL) andCH₂Cl₂ (20 mL), separate the layers, extract the aqueous layer withCH₂Cl₂ (2×20 mL), wash the combined organic layer with brine,concentrate and purify the mixture with column chromatography usingCH₂Cl₂ and CH₃OH with NH₃ (98:2) to give 0.22 g product.

[0221] Step 2: Dissolve the product of Step 1 (0.22 g, 0.25 mmol) in dryTHF (2 mL), treat the solution with tetrabutylammonium fluoride (1 M,0.3 mL, 0.30 mmol) at 0° C. Allow the mixture to warm up to 23° C. over30 min and stir additional 1 h. Dilute with EtOAc (50 mL) and water (50mL), extract aqueous phase with EtOAc (2×40 mL) and concentrate thecombined organic layer. Purify by column chromatography using EtOAc andhexane (1:1) to obtain 0.15 g product.

[0222] Step 3: Dissolve the product of Step 2 (140 mg, 0.32 mmol) inEtOAc (3 mL), prepare a solution of NaBr (33 mg, 0.32 mmol) in 3 mL ofsaturated aqueous NaHCO₃, and add to the reaction vessel. Add TEMPO (1mg). With vigorous stirring, add 1 mL of commercial bleach (ca 0.7 M,0.7 mmol). Add saturated aqueous Na₂S₂O₃ (3 mL), isolate the organiclayer and extract the aqueous layer with CH₂Cl₂. Combine the organiclayers, wash with saturated aqueous NaHCO₃, and concentrate to give 140mg aldehyde as the product.

[0223] Step 4: Hydrogenate the product of Preparation 3 using aprocedure similar to that described in Example 1, Step 3. React theresulting deprotected product with the aidehyde from Step 3 in a similarprocedure to that described in Example 1, Step 3, to yield the titleproduct.

[0224] Example 7B-7F:

[0225] Prepare the compounds by a procedure similar to Example 7A usingappropriate aryl acids.

EXAMPLE 8

[0226]

Ex. R²⁹ HRMS (FAB, M + H⁺) 8A

Calc'd: 642.1572 found: 642.1555 8B

Calc'd: 656.1729 found: 656.1714 8C

Calc'd: 684.1678 found: 684.1660 8D

Calc'd: 746.1834 found: 746.1837 8E

Calc'd: 742.1733 found: 742.1734 8F

LRMS 699 (M + 1) 8F

Calc'd: 728.1940 found: 728.1934 8H

Calc'd: 714.1784 found: 714.1788 8I

Calc'd: 713.1943 found: 713.1944 8J

Calc'd: 701.1757 found: 701.1767 8K

Calc'd: 734.1504 found: 734.1523 8L

Calc'd: 721.1300 found: 721.1308

[0227] Example 8A:

[0228] Step 1: Treat the product of Preparation 8 (240 mg, 0.88 mmol) inCH₂Cl2 (3 mL) with 2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate (350mg, 1.24 mmol), and stir for 14 h. Add water and CH₂Cl₂, and extract theaqueous layer with CH₂Cl₂ (2×20 mL), wash the combined organic layerwith brine, concentrate and purify the mixture with columnchromatography using CH₂Cl₂ and CH₃OH with NH₃ (98:2) to give 149 mgproduct.

[0229] Step 2: Treat the product of Step 1 using a procedure similar toStep 3A of Example 1. Alternatively, for optically pure product, use aprocedure similar to Step 3B of Example 1.

[0230] Step 3: Treat the product of Step 2 (190 mg, 0.24 mmol) in THF (2mL) with tetrabutylammonium fluoride (1 M, 0.5 mL, 0.50 mmol), and stirfor 3 h. Add water and CH₂Cl₂, and extract the aqueous layer with CH₂Cl₂(2×20 mL), wash the combined organic layer with brine, concentrate andpurify the mixture with column chromatography using CH₂Cl₂ and CH₃OHwith NH₃ (95:5) to give 119 mg of the title product.

[0231] Example 8B:

[0232] Step 1: Treat the product of Preparation 8 (320 mg, 1.17 mmol) inTHF (3 mL) with NaH (60% in mineral oil, 56 mg, 1.41 mmol) at 0° C. for15 min, and add CH₃l (88 mL, 1.41 mmol). After stirring for 2 h, quenchwith water and CH₂Cl₂, extract the aqueous layer with CH₂Cl₂ (2×20 mL),wash the combined organic layer with brine, concentrate and purify themixture with column chromatography using CH₂Cl₂ and CH₃OH with NH₃(95:5) to give 180 mg product.

[0233] Step 2: Treat the product of Step 1 using a procedure similar toStep 3B of Example 1 to give the title compound.

[0234] Example 8C:

[0235] Step 1: Treat the product of Preparation 8 (250 mg, 0.92 mmol) inCH₂Cl₂ (3 mL) with ET₃N and acetyl chloride (90 mg, 1.19 mmol), and stirfor 2 h. Add water and CH₂Cl₂, extract the aqueous layer with CH₂Cl₂(2×20 mL), wash the combined organic layer with brine, concentrate andpurify the mixture with column chromatography using CH₂Cl₂ and CH₃OHwith NH₃ (95 :5) to give 230 mg product.

[0236] Step 2: Treat the product of Step 1 using a procedure similar toStep 3 of Example 1 to give the title compound.

[0237] Examples 8D-F and 8K:

[0238] Prepare the desired compounds by a procedure similar to thatdescribed in Example 8C using appropriate the acyl halide, isocyanate orsulfonyl chloride.

[0239] Examples 8G and 8H:

[0240] Prepare the desired compounds by a procedure similar to thatdescribed in example 8B using appropriate alkyl halides.

[0241] Examples 8I and 8J:

[0242] Prepare the target compounds by stirring a mixture of NH₄OH andNH₄Cl with the products Examples 8G and 8H in CH₃OH for 48 h.

[0243] Example 8L:

[0244] Treat the product of Preparation 8 (250 mg, 0.92 mmol) in1,4-dioxane (39 mL) with sulfamide (0.6 g, 6.3 mmol), and reflux for 24h at 80° C. Concentrate and purify the mixture with columnchromatography using CH₂Cl₂ and CH₃OH with NH₃ (95:5) to give 150 mg ofthe title product.

EXAMPLE 9

[0245]

Ex. R²⁹ HRMS (FAB, M + H⁺) 9A

Calc'd: 656.1365 found: 656.1357 9B

Calc'd: 670.1521 found: 670.1514 9C

Calc'd: 728.1576 found: 728.1571 9D

Calc'd: 714.1420 found: 714.1438 9E

Calc'd: 769.1842 found: 769.1838 9F

Calc'd: 713.1580 found: 713.1569

[0246] Example 9A:

[0247] Treat the product of Preparation 9 using a procedure similar toStep 3A of Example 1. Alternatively, prepare the optically pure compoundusing a procedure similar to Example 1, Step 3B.

[0248] Example 9B:

[0249] Treat the product of Preparation 9 using a procedure similar toExample 8B to give the target compound.

[0250] Example 9C:

[0251] Treat the product of Preparation 9 using a procedure similar toExample 8H to give the title compound.

[0252] Example 9D:

[0253] Hydrolyze the product of Example 9C using a procedure similar tothat described in Example 4A.

[0254] Examples 9E - 9G:

[0255] Acylate the product of Example 9D using a procedure similar tothat described in Example 6G with appropriate amines.

EXAMPLE 10

[0256]

Ex. R²⁹ HRMS (FAB, M + H⁺) 10A

*LRMS: 730.1 (M + 1) 10B

Calc'd: 714.1420 found: 714.1438 10C

Calc'd: 769.1842 found: 769.1848 10D

Calc'd: 713.1580 found: 713.1593 10E

Calc'd: 727.1736 found: 727.1733 10F

Calc'd: 741.1893 found: 741.1882 10G

Calc'd: 799.1770 found: 799.1767 10H

Calc'd: 783.1998 found: 783.2006 10I

Calc'd: 767.2049 found: 767.2054

[0257] Example 10A:

[0258] Prepare title compound by a procedure similar to Preparation 9using L-N-Boc-aspartic acid methyl ester in place of glycine methylester.

[0259] Examples 10B -10I:

[0260] Prepare the desired compounds by standard hydrolysis andacylation procedures similar to those described in Examples 9D-9G.

EXAMPLE 11

[0261]

Ex. R²⁹ HRMS (FAB, M + H⁺) 11A

Calc'd: 713.1580 found: 713.1593 11B

Calc'd: 783.1998 found: 783.2012 11C

Calc'd: 767.2049 found: 767.2061 11D

Calc'd: 769.1842 found: 769.1817

[0262] Examples 11A -11 D:

[0263] Prepare the desired compounds by procedures similar to Example10, using D-N-Boc-aspartic acid benzyl ester in place ofL-N-Boc-aspartic acid methyl ester.

EXAMPLE 12

[0264]

Ex. R²⁶ HRMS (FAB, M + H⁺) 12A

Calc'd: 628.1416 found: 628.1434 12B

Calc'd: 714.1784 found: 714.1765 12C

Calc'd: 686.1471 found: 686.1482 12D

Calc'd: 687.1601 found: 687.1603 12E

Calc'd: 755.2049 found: 755.2047 12F

Calc'd: 714.1784 found: 714.1776 12G

Calc'd: 728.1940 found: 728.1945 12H

Calc'd: 713.1943 found: 713.1945 12I H₃C— Calc'd: 642.1572 found:642.1562

[0265] Example 12A:

[0266] Step 1: Dissolve the product of Preparation 8, Step 1 (2.7 g, 8.1mmol) in CH₂Cl₂ (40 mL), treat with 4 M HCl in dioxane (40 mL, 160 mmol)and stir for 2 h. Remove solvent under reduced pressure to yield a crudeproduct. Re-dissolve the product in THF (45 mL), treat withcarbonyidiimidazole (2.26 g, 13.9 mmol) and reflux for 24 h. Removesolvent under reduced pressure and dilute with CH₂Cl₂ and NaHCO₃.Separate the organic layer, concentrate and purify the mixture withcolumn chromatography using CH₂Cl₂ and CH₃OH with NH₃ (96:4) to give 1.8g product.

[0267] Step 2: Treat the product of Step 1 by a procedure similar toExample 1, Step 3 to give the product.

[0268] Example 12B:

[0269] Step 1: Use a procedure described in Preparation 11, substituting2-amino-ethanol for 3-amino-1-propanol to obtain the product.

[0270] Step 2: Treat the product of Step 1 by a procedure similar toPreparation 12A using glycine ethyl ester in place of methylamine.

[0271] Step 3: Treat the product of Step 2 by a procedure similar toExample 1, Step 3, using acid deprotection (HCl in CH₂Cl₂) in place ofhydrogenation.

[0272] Example 12C:

[0273] Hydrolyze the product of Example 12B in a manner similar toExample 4A to give the desired product.

[0274] Examples 12D and 9E:

[0275] Treat the product of Example 12C by an amidation proceduresimilar to that described in Example 4E to give the title product.

[0276] Example 12F:

[0277] Step 1: Use the procedure of Preparation 11, substituting2-aminoethanol for 3-amino-1-propanol.

[0278] Step 2: Treat the product of Step 1 using a procedure similar toExample 6L, Steps 2-4, to obtain the title compound.

[0279] Examples 12G-12H:

[0280] Treat the product of Example 12F using a procedure similar toExamples 6M and 6N to obtain the title compounds.

[0281] Example 12I:

[0282] Treat the product of Example 12F, Step 1, using a proceduresimilar to Example 6P to obtain the title compound.

EXAMPLE 13

[0283]

Ex. Z MS 13A

Calc'd: 643.1412 found: 643.1419 13B

Calc'd: 659.1362 found: 659.1363

[0284] Example 13A:

[0285] Treat the product of Preparation 10 using a procedure similar toExample 1, Step 3 to yield the title compound.

[0286] Example 13B:

[0287] Treat the product of Example 13A using a procedure similar tothat described in Preparation 12I-12L to yield the title compound.

EXAMPLE 14

[0288]

Ex. R1 MS (FAB): m/e 14A

Calc'd: 757.1954 found: 757.1945 14B

Calc'd: 771.2111 found: 771.2099 14C

Calc'd: 829.2278 found: 829.2269

[0289] Example 14A:

[0290] Step 1: Treat3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-[[hydroxyimino]-6-methyl-5-heptenyl]-N-methylbenzamide(4.2g, 8.6 mmol) in dry DMF(40 mL) at 0° C. with KHMDS (0.5 M, toluene,19 mL) keeping the internal temperature to <50° C. After stirring for 30min, add bromoacetonitrile (655 μL, 9.4 mmol) and stir for 10 min. Pourthe mixture into EtOAc (150 mL)/sat NaHCO₃ (75 mL). Extract the aqueouslayer, wash the combined organic layers with brine, dry with Na₂SO4 andconcentrate in vacuo. Purify by silica gel chromatography eluting withhexane/EtOAc to obtain 3.83 g (85%) of the nitrile as a colorless foam.

[0291] Step 2: Cool a solution of the olefin (3.83 g) from step 1 ( indry CH₂Cl₂ (50 mL) to −78° C. and treat with ozone for 7 min. Treat thesolution with dimethylsulfide (5.3 mL, 72.6 mmol, 10 eq). Allow thesolution to warm to 23° C. and stir for 2.5 h. Dilute the solution withCH₂Cl₂ (50 mL) and wash with 10% Na₂S₂O₄. Wash the organic layers withbrine, dry with Na₂SO₄ and concentrate in vacuo to give the aldehyde.

[0292] Step 3: Treat the product of step 2 using a procedure similar toExample 6FF.

[0293] Step 4: Treat the product of step 3 using a procedure similar tothat of Example 6GG to obtain the corresponding hydroxyamidine.

[0294] Example 14B:

[0295] Treat Example 14A using a procedure similar to that of Example14A, step 1, using LHMDS in place of KHMDS and CH₃l as the alkylatingagent to obtain the title compound.

[0296] Example 14C:

[0297] Treat the product of Example 14A using a procedure similar tothat of Example 14A, step 1, and then step 4 to give the desiredcompound.

EXAMPLE 15

[0298]

Ex. R¹ HRMS (FAB): m/e 15A

Calc'd: 700.1739 found: 771.2099 15B

Calc'd: 685.1630 found: 685.1627

[0299] Example 15A:

[0300] Use a procedure similar to that of Example 14A using the productof example 60, step 1 as the piperidine in the reductive amination forstep 3. Proceed to step 4 to give the title compound.

[0301] Example 15B:

[0302] Use a procedure similar to that for Example 6A usingmethylbromoacetate in place of bromoacetonitrile. Proceed through thereductive amination with the product of Example 6O, step 1 to give themethyl ester. Stir the resulting methyl ester with CH₃OH saturated withNH₃ for 18 h. Concentrate in vacuo and purify by silica gelchromatography to give the title compound.

EXAMPLE 16

[0303]

[0304] Treat the product of Example 14A, step 3 to a procedure similarto that of Example 6GG to give the title compound. HRMS (FAB, m/e):Calc'd: 772.2063; found: 772.2059.

EXAMPLE 17

[0305]

[0306] Step 1: Using a procedure similar to Preparation 12C-12H andsubstituting glycine methylester for the appropriate amine, prepare thecorresponding cyclic urea/Boc piperidine.

[0307] Step 2: Using a procedure similar to Example 4A, hydrolyze themethyl ester to the carboxylic acid.

[0308] Step 3: Using a procedure similar to Example 4B to prepare thecorresponding pyrrolidine amide.

[0309] Step 4: Using a procedure similar to Preparation 12A, step 3,deprotect the Boc group and isolate the free base of the resultingpiperdine.

[0310] Step 5: Use the product of step 4 in a procedure similar toExample 14A, steps 3 and 4 to prepare the title compound. HRMS (FAB,M+H⁺): Calc'd: 811.2424; found: 811.2441.

EXAMPLE 18

[0311]

Ex. R²⁶ HRMS (FAB, M + H⁺) 18A H Calc'd: 676.1416 Found: 676.1389 18BCH₃— Calc'd: 692.1543 Found: 692.1558 18C

Calc'd: 748.1627 Found: 748.1621 18D

Calc'd: 734.1471 Found: 734.1487

[0312] Example 18A:

[0313] Treat 4-(2-keto-1-benzimidazolinyl)-piperidine and the product ofPreparation 2 using the procedure of Example 2, Step 2, to give thetitle compound.

[0314] Examples 18B-18D:

[0315] Treat the product of Example 18A using the procedure in Examples9B, 9C and 9D to give the title compounds.

EXAMPLE 19

[0316]

Ex. R²⁶ HRMS (FAB, M + H⁺) 19A CH₃O(CH₂)₂- Calc'd: 772.1852 Found:772.1859 19B CH₃O(CH₂)₂NHC(O)CH₂- Calc'd: 805.2206 Found: 805.2195

[0317] Example 19A:

[0318] Step 1: Treat Boc-4-(2-keto-1-benzimidazolinyl)-piperidine (3.0g, 9.46 mmol) with a preheated mixture of NaOH (1.14 g, 28.2 mmol),K₂CO₃ (2.61 g, 18.9 mmol) and nBuNHSO₄ (0.305 g, 0.9 mmol) in toluene(75 ml) for 30 min., add 2-bromomethoxyethane (1.33 ml, 14.2 mmol) andheat at 80° C. for an additional hour. Upon cooling, treat the mixturewith water and EtOAc, adjust pH to 7 using 10% citric acid. Extract withEtOAc, dry the organic layer with Na₂SO₄ and concentrate in vacuo togive a crude product.

[0319] Step 2: Deprotect the Boc group of the product of Step 1 using asimilar procedure as in Preparation 12A, Step 3. Treat the product usinga procedure similar to Example 1, Step 3B, using the correspondingoptically pure aldehyde (prepared as in Preparation 1) to give thedesired product.

[0320] Example 19B:

[0321] Use a procedure similar to that of Example 18C using thecorresponding aldehyde (prepared as in Preparation 1) to give a product.Dissolve the product (0.5 g, 0.655 mmol) in 2-methoxyethylamine (10 ml),and heat at 60° C for 24 h. Upon cooling, treat the mixture with waterand EtOAc. Extract with EtOAc, dry the organic layer with Na₂SO₄ andconcentrate in vacuo to give a crude product. Purify by silica gelchromatography, eluting with CH₂Cl₂/CH₃OH gradient elution (99:1-97:3)to obtain 0.277 g of the desired product.

[0322] Compounds of formula I have been found to be antagonists of NK₁and/or NK₂ and/or NK₃ receptors, and are therefore useful in treatingconditions caused or aggravated by the activity of said receptors.

[0323] The in vitro and in vivo activity of the compounds of formula Ican be determined by various procedures known in the art, such as a testfor their ability to inhibit the activity of the NK₁ agonist SubstanceP, an isolated hamster trachea NK₂ assay, a test of the effect of NK₁antagonists on Substance P-induced airway microvascular leakage,measurement of NK₂ activity in vivo in guinea pigs, measurement ofbronchoconstriction due to NKA, and neurokinin receptor bindingassay(s). NK₃ activity is determined by following a procedure similar tothat described in the literature, e.g., Molecular Pharmacol, 48 (1995),p. 711-716. Typical procedures for determining NK₁ and NK₂ activity aredescribed in U.S. Pat. No. 5,696,267, incorporated herein by reference.

[0324] % Inhibition of neurokinin agonist activity is the differencebetween the percent of maximum specific binding (MSB) and 100%. Thepercent of MSB is defined by the following equation, wherein “dpm” isdisintegrations per minute:${\% \quad {MSB}} = {\frac{\left( {{dpm}\quad {of}\quad {unknown}} \right) - \left( {{dpm}\quad {of}\quad {nonspecific}\quad {binding}} \right)}{\left( {{dpm}\quad {of}\quad {total}\quad {binding}} \right) - \left( {{dpm}\quad {of}\quad {nonspecific}\quad {binding}} \right)} \times 100}$

[0325] It will be recognized that compounds of formula I exhibit NK₁,NK₂ and/or NK₃ antagonist activity to varying degrees, e.g., certaincompounds have strong NK₁ antagonist activity, but weaker NK₂ and NK₃antagonist activity, while others are strong NK₂ antagonists, but weakerNK₁ and NK₃ antagonists. While compounds with approximate equipotencyare preferred, it is also within the scope of this invention to usecompounds of with unequal NK₁/NK₂/NK₃ antagonist activity whenclinically appropriate.

[0326] Using the test procedures known in the art, the following data (%inhibition or Ki) were obtained for preferred and/or representativecompounds of formula I : Ki (NK₁) Ki (NK₂) Ki (NK₃) Ex. (nM) (nM) (nM) 5B 0.9 2.8 —  6E 1.0 1.0 1.5  6K 0.5 0.8 0.5  6Y 0.4 0.4 0.4  8A 1.10.7 1.2 10B 2.9 28.9 34.6 11A 0.8 1.0 1.9  7F 1.8 0.4 3.8 16 0.4 0.4 0.718A 1.2 1.0 9.8  6M 0.9 0.5 0.3  6S 1.0 0.9 2.1

[0327] Compounds of the present invention exhibit a range of activity:percent inhibition at a dosage of 1 μM ranges from about 0 to about 100%inhibition of NK₁ and/or about 0 to about 100% inhibition of NK₂.Preferred are compounds having a Ki<20 nM for the NK₁ receptor. Alsopreferred are compounds having a Ki<20 nM for the NK₂ receptor. Anothergroup of preferred compounds are those having a Ki<20 nM for each of theNK₁ and NK₂ receptors.

We claim:
 1. A compound represented by the structural formula

or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1, 2 or3; b and d are independently 0, 1 or 2; R is H, C₁₋₆ alkyl, —OR⁶ or —F;A is ═N—OR¹ or ═N—N(R²)(R³); when d is not 0, X is a bond, —C(O)—, —O—,—NR⁹—, —S(O)_(e)—, —N(R⁶)C(O)—, —C(O)N(R⁶)—, —OC(O)NR⁶—, —OC(═S)NR⁶—,—N(R⁶)C(═S)O—, —S(O)₂N(R⁶)—, —N(R⁶)S(O)₂—, —N(R⁶)C(O)O—, —OC(O)— or—N(R⁶)C(O)NR⁷—; and when d is 0, X is a bond or —NR⁶—; T is H, R⁴-aryl,R⁴-heterocycloalkyl or R⁴-heteroaryl; Q is R⁵-phenyl, R⁵-naphthyl orR⁵-heteroaryl; R1 is H, C₁₋₆ alkyl, —(C(R⁶)(R⁷))_(n)—G, —G²,—(C(R⁶)(R⁷))_(p)—M—(C(R¹³)(R¹⁴))_(n)—G or—(C(R⁶)(R⁷))_(p)—M—(R⁴-heteroaryl); R² and R³ are independently selectedfrom the group consisting of H, C₁₋₆ alkyl, —(C(R⁶)(R⁷))_(n)—G, —G² and—S(O)_(e)R¹³⁻; or R² and R³, together with the nitrogen to which theyare attached, form a ring of 5 to 6 members, wherein 0, 1 or 2 ringmembers are selected from the group consisting of —O—, —S— and —N(R¹⁹)—;R⁴ and R⁵ are independently 1-3 substituents independently selected fromthe group consisting of H, halogeno, —OR⁶, —OC(O)R⁶, —OC(O)N(R⁶)(R⁷),—N(R⁶)(R⁷), C₁₋₆ alkyl, —CF₃, —C₂F₅, —COR⁶, —CO₂R⁶, —CON(R⁶)(R⁷),—S(O)_(e)R¹³, —CN, —OCF₃, —OCHF₂, —NR⁶CO₂R¹⁶, —NR⁶COR⁷, —NR⁸CON(R⁶)(R⁷),NO₂, —N(R⁶)S(O)₂R¹³ or —S(O)₂N(R⁶)(R⁷); or adjacent R⁴ substituents oradjacent R⁵ substituents can form a —O—CH₂—O—group; R⁶, R⁷, R⁸, R¹³ andR¹⁴ are independently selected from the group consisting of H, C₁₋₆alkyl, C₂-C₆ hydroxyalkyl, C₁-C₆ alkoxy-C₁-C₆ alkyl, R¹⁵-phenyl, andR¹⁵-benzyl; R⁹ is independently selected from the group consisting of R⁶and —OR⁶⁻; or R⁶ and R⁷, or R⁷ and R⁹, together with the nitrogen towhich they are attached, form a ring of 5 to 6 members, wherein 0, 1 or2 ring members are selected from the group consisting of —O—, —S—and—N(R¹⁹)—; R^(6a), R^(7a), R^(8a), R^(9a), R¹⁰ and R^(10a)areindependently selected from the group consisting of H and C₁₋₆ alkyl;R¹⁵ is 1 to 3 substituents independently selected from the groupconsisting of H, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C_(1-C) ₆ alkylthio,halogeno, —CF₃, —C₂F₅, —COR¹⁰, —CO₂R¹⁰, —C(O)N)R¹⁰)₂, —S(O)_(e) R^(10a),—CN, —N(R¹⁰)COR¹⁰, —N(R¹⁰)CON(R¹⁰)₂ and —NO₂; R¹⁶ is C₁₋₆ alkyl,R¹⁵-phenyl or R¹⁵-benzyl; R¹⁹ is H, C₁-C₆ alkyl, —C(O)N(R¹⁰)₂ or—CO₂R¹⁰; n and p are independently 1-6; G is selected from the groupconsisting of H, R⁴-aryl, R⁴-hetero-cycloalkyl, R⁴-heteroaryl,R⁴-cycloalkyl, —CH₂F, —CHF₂, —CF₃, —OR⁶, —N(R⁶)(R⁷), —COR⁶, —CO₂R⁶,—CON(R⁷)(R⁹), —S(O)_(e)R¹³, —NR⁶CO₂R¹⁶, —NR⁶COR⁷, —NR⁸CON(R⁶)(R⁷),—N(R⁶)S(O)₂R¹³, —N(R⁶)S(O)₂N(R³³)(R³⁴), —S(O)₂N(R⁶)(R⁷), —OC(O)R⁶,—OC(O)N(R⁶)(R⁷), —C(═NOR⁸)N(R⁶)(R⁷), —C(═NR²⁵)N(R⁶)(R⁷),—N(R⁸)C(═NR²⁵)N(R⁶)(R⁷), —CN, —C(O)N(R⁶)OR⁷, and—C(O)N(R⁹)—(R⁴-heteroaryl), provided that when n is 1, G is not —OH or—N(R⁶)(R⁷); M is selected from the group consisting of a double bond,—O—, —N(R⁶)—, —C(O)—, —C(R⁶)(OR⁷)—, —C(R⁸)(N(R⁶)(R⁷))—, —C(═NOR⁶)N(R⁷)—,—C(N(R⁶)(R⁷))═NO—, —C(═NR²⁵)N(R⁶)—, —C(O)N(R⁹)—, —N(R⁹)C(O)—,—C(═S)N(R⁹)—, —N(R⁹)C(═S)— and —N(R⁶)C(O)N(R⁷)—, provided that when n is1, G is not OH or —NH(R⁶); and when p is 2- 6, M can also be—N(R⁶)C(═NR²⁵)N(R⁷)— or —OC(O)N(R⁶)—; G² is R⁴-aryl,R⁴-heterocycloalkyl, R⁴-heteroaryl, R⁴-cycloalkyl, —COR⁶, —CO₂R¹⁶, —S(O)₂N(R⁶)(R⁷) or —CON(R⁶)(R⁷); e is 0, 1 or 2, provided that when e is 1or 2, R¹³ and R^(10a) are not H; R²⁵ is H, C₁ -C₆ alkyl, —CN, R¹⁵-phenylor R¹⁵-benzyl;

g, h and j are independently 0-2; k is 1-4; X¹ is —O—, —S— or —NR⁹—; Jis ═O, ═S, ═NR⁹, ═NCN or ═NOR¹; J¹ and J² are independently selectedfrom the group consisting of two hydrogen atoms, ═O, ═S, ═NR⁹ and ═NOR¹;R²⁶, R²⁷ and R²⁹ are independently selected from the group consisting ofH, C₁₋₆ alkyl, —(C(R⁶)(R⁷))n—G, —G², —C(O)—(C(R⁸)(R⁹))_(n)—G and—S(O)_(e)R¹³; R²⁸ is H, —(C(R⁶)(R⁷))_(t)—G or —CON(R⁶)(R⁷); t is 0, 1, 2or 3, provided that when j is 0, t is 1, 2 or 3; R³⁰ is 1-3 substituentsindependently selected from the group consisting of H, halogeno, —OR⁶,—OC(O)R⁶, —OC(O)N(R⁶)(R⁷), —N(R⁶)(R⁷), C₁₋₆ alkyl, —CF₃, —C₂F₅, —COR⁶,—CO₂R⁶, —CON(R⁶)(R⁷), —S(O)_(e)R¹³, —CN, —OCF₃, —NR⁶CO₂R¹⁶, —NR⁶COR⁷,—NR⁸CON(R⁶)(R⁷), NO₂, —N(R⁶)S(O)₂R¹³ or —S(O)₂N(R⁶)(R⁷); or adjacent R³⁰substituents can form a —O—CH₂—O—group; R³¹ is independently selectedfrom the group consisting of H and C₁-C₆ alkyl; R³² is independentlyselected from the group consisting of H, —OH and C ₁-C₆ alkoxy; and R³³and R³⁴ are independently selected from the group consisting of H, C₁-C₆alkyl, R¹⁵-phenyl and R¹⁵-benzyl.
 2. A compound of claim 1 wherein d isnot 0 and X is —O—, —C(O)—, a bond, —NR⁹—, —S(O)_(e)—, —N(R⁹)C(O)—,—C(O)NR⁶ or —OC(O)NR⁶—.
 3. A compound of claim 1 wherein T is R⁴-aryl orR⁴-heteroaryl.
 4. A compound of claim 1 wherein Q is R⁵-phenyl,.
 5. Acompound of claim 1 wherein Z is

g and h are each 1; J is ═O; j is 0; k is 1 or 2; and R²⁸ is H.
 6. Acompound of claim 1 wherein d is not 0 and X is —O—, —C(O)—, a bond,—NR⁹—, —S(O)_(e)—, —N(R⁶)C(O)—, —C(O)NR⁶ or —OC(O)NR⁶—; T is R⁴-aryl orR⁴-heteroaryl; Q is R⁵-phenyl; Z is

g and h are each 1; J is ═O; j is 0; k is 1 or 2; and R²⁸ is H.
 7. Acompound of claim 6 wherein A is ═N—OR¹, X is —N(R⁶)C(O)—, T is R⁴—aryl;Q is R⁵—phenyl; and R^(6a), R^(7a), R^(8a) and R^(9a) are each H.
 8. Acompound of claim 7 wherein Z is

and k is 1 or
 2. 9. A compound of claim 1 selected from the group ofcompounds represented by the formula

wherein Z, R¹ and T are as defined in the table: Z R¹ T

—CH₃

—CH₃

—CH₂C(O)NH₂

—CH₂C(NH₂)═NOH

—CH₂C(NH₂)═NOH

—CH₂C(NH₂)═NOH

—CH₂C(NH₂)═NOC₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃

—CH₂C(NH₂)═NOH

—CH₃

—CH₃

—CH₃

—CH₃

—CH₃


10. A pharmaceutical composition comprising an effective amount of acompound of claim 1 and a pharmaceutically acceptable carrier.
 11. Amethod of treating respiratory diseases, inflammatory diseases, skindisorders, ophthamalogical disorders, addictions, central nervous systemconditions, gastrointestinal disorders, bladder disorders,atherosclerosis, fibrosing disorders and obesity, comprisingadministering an effective amount of a compound of claim 1 to a mammalin need of such treatment.
 12. A method of treating chronic lungdisease, bronchitis, pneumonia, asthma, allergy, cough, bronchospasm,arthritis, psoriasis, atopic dermatitis, contact dermatitis, retinitis,ocular hypertension, cataracts, alcohol dependence, stress relateddisorders, anxiety, migraine, epilepsy, nociception, emesis, depression,psychosis, schizophrenia, Alzheimer's disease, AIDs related dementia,Towne's disease, Crohn's disease, colitis, bladder disorder,atherosclerosis, fibrosing disorders or obesity, comprisingadministering an effective amount of a compound of claim 1 to a mammalin need of such treatment.